Cystic fibrosis (CF) is an autosomal recessive disorder caused by dysfunction of the CF Transmembrane Conductance Regulator (CFTR) channel. The care of patients with CF has rapidly evolved with the development of CFTR modulators, novel pharmaceuticals that address the basic CF defect and restore CFTR function. Despite the success of one of these, the potentiator ivacaftor, there is still pronounced variance in drug efficacy, as measured in individuals? phenotypic response to therapy and their in vitro cellular response when assessed with cell-based biomarkers. Ivacaftor is metabolized by cytochrome P450 (CYP3A enzymes), which are responsible for both hepatic and tissue-specific metabolism, including in airway epithelia. Genetic variation in these enzymes cause altered activity, resulting in variation in efficacy in many drugs. The preliminary data demonstrate CYP3A variants may be associated with drug efficacy, and the ability to detect ivacaftor metabolism in vitro in individual patients? epithelia that the applicant personally co-developed. To maximize efficacy of ivacaftor, and thus, any therapy including it, it is essential to understand pharmacogenetics and effect of variability of CYP3A enzyme activity on the metabolism of ivacaftor. The Specific Aims are: 1) conduct a pilot study in people to determine population pharmacokinetics of ivacaftor in plasma and epithelia, and correlate drug exposure with drug response 2) to determine frequencies of genetic variants of these enzymes in the CF population and measure association with clinical efficacy; 3) compare the contribution of CYP3A isoforms to ivacaftor metabolism and understand impact in primary epithelial cells on CFTR activity. Ivacaftor is a significant component of many combination therapies, so understanding its variation in metabolism and impact on efficacy is the first key step to understanding pharmacogenetics in complex combinations, and will set the stage for an independent career focused on precision-directed therapeutics in CF. The applicant has dedicated her professional life to becoming a physician-scientist, studying pediatric pulmonology in general and cystic fibrosis in particular. To achieve this, she accepted a faculty position at the University of Alabama at Birmingham, where a supportive research environment in the Department of Pediatrics and School of Medicine, as well as the Gregory Fleming James Cystic Fibrosis Research Center, has made career advancement and approach to independence possible. To accomplish the goals of this research, the candidate has assembled a mentoring team with decades of experience in clinical trials, pharmacology, genetics, statistics, pharmacogenetics, and drug metabolism to advise and guide her during her career development. She also proposes to undertake formal training in pharmacology, advanced statistics, clinical trial conduct, and genetics to complement her prior medical and graduate studies and acquire the relevant skills to transition to independence.